Hydroxy-lower-alkyl-bis(cyclohexylpropyl) amines, salts thereof, and preparation thereof



United States Patent.

HYDROXY' LOWER ALKYL BIS(CYCLOHEXYL- PROPYL)AMINES, SALTS THEREOF, AND. PREP- ARATION THEREOF William B. Dickinson, Loudonville, andBernard L. Zenitz, Delmar, N. Y., assignors' to Sterling Drug Inc New York, N. Y., a corporation of Delaware No Drawing. Application June 14, 1954 Serial.No.- 436,710

14 Claims. (Cl. 260-563) This invention relates to a' new series of cycloalkylpropyl amines bearing a hydroxylated alkyl group attached to the nitrogen atom, and to a process for the preparation thereof.

A particular aspect of the invention relates to hydroxylower-'alkyl-bis(3-cyclohexylpropyl)amines and their acidiaddition salts, said compounds thus having the formula wherein R ishydrogen or a lower-alkyl group and'R' is alower-alkyl group bearing from one to three hydroxy groups, and acid-addition salts thereof.

In the above formula the group R represents a hydrogen atom or a lower-alkyl group. When R is a lower-alkyl group it can be. in any one of the 2-, S-and 4-positions with respect to the propyl side chain, and contains from one to about four carbon atoms, thus'including methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.

In the above formula the group R represents a loweralkyl group having from one to about eight carbon atoms and bearing from one to three hydroxy groups. The lower-alkyl group can be straight orbranched, and the hydroxy group or groups can be located anywhere along the chain, except that two hydroxy groups cannot be attachedto the same carbon atom. Exemplary of the group R are hydroxymethyl, Z-hydroxyethyl, 3-hydroxypropyl, 2+hydroxypropyl, 2-hydroxy-l-methylethyl, Z-hydroxy-1,2-dimethylethyl, 2,3-dihydroxypropyl, 2,3,4-tri-. hydroxybutyl, tris(hydroxymethyl)methyl, 3.-hydroxypentyl, 3,5-dihydroxyhexyl, 8-hydroxyoctyl, tris(2-hydroxy ethyl)methyl, and the like.

The compounds of the invention are prepared by the following reaction:

where X is halogen selected from chlorine; bromine-and iodine, preferably bromine. The reaction is carried out by heatingthc reactantsin an inert solvent in the presence of an acid acceptor such as sodium carbonate, designed to take up the hydrogen halide formed. The first substance produced in the reaction mixture is thesecondary'amine, RC H CH CI-I CH NHR', which then reacts further with another mole of the cyclohexylpropyl halide'to give the tertiaryamine. Frequently the reaction mixture will be found to contain a mixture of the secondary and tertiary amines, the relative amounts of each dependingupon the conditions of time and temperature used during thereaction. Higher temperatures and longer times favor the formation ofthe tertiary amine. The secondary and'tertiary amines canbe separated by. fractional. distillation, or by fractional crystallization or selectiveextraction of their acid-addition salts.

) ice Alternatively a tertiary amine of formula I can beprepared'by. condensation of thesecondary amine,

with an alkyl halide R'X. The secondary amine,

(RCs 1o aC 2C 2)2 H,

can be prepared by diallcylation of ammonia with or by hydrogenolysis of'thev benzyl substituted tertiary amine, (RC H CH CH CH NCH C HS, in turn prepared'by. alkylationof .benzylamine with Compounds bearing a hydroxyl group in the groupv R on thegcarbonatom immediately adjacent to the'nitrogen atom are preferably prepared by analternative procedure; i.-e., by reactionofanaldehyde with the secondary amine, (RC H CH2CH CH NH, in which the latter addsacross the double; bondiof the; aldehyde as in the formation of aldehyde-ammonia; Forexample, formaldehyde reacts with thersecondary aminev to give. acompound where R is hydroxymethyl,-;viz.

In compounds whereR is :lower alkyl a-number of isomeric substances; ispossible. The lower-alkyl group may be in the ,2.-, 3"- or4 -position and in thepositioncis or trans with'respect to the: propyl side chain. Mixtures of these isomers are often encountered during the course of synthesis. It is not necessary to separate these isomers in orderto obtain useful and active products, but the separation maybe carried outifdesired and as illustrated in the examples below. Our new compounds are useful eitherin, the free; base form or in the form of non-toxic acid-additionsalts; and these salts are within the purview of the invention. The acids Which-can beused to prepare acid-additionsalts are preferably those which produce when combinedwith the free base, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that thebeneficial physiological properties 'inherentin the free base are not vitiated by side effects ascribable-to the anions. Appropriate acid-addition salts are those derived from mineral'acids such' as hydrochloric acid, hydrobromic acid, hydriodic acid, nitricacid, phosphoric acid and sulfuric acid; and organicacids such, asacetic acid, citric acid, tartaric acid, lactic acid, ethanesulfonicacid, quinic acid, sulfamic acid, and the like, giving the hydro chloride, hydrobromide, hydriodide, nitrate, phosphate, or acid phosphate, sulfate or bisulfate, acetate, citrate'or acid citrate, tartrate or bitartrate, lactate, ethanesulfonate, quinate, and sulfamate salts, respectively.

The. compounds of our invention are useful as coronary dilators. When'introduced into the mammalian. organism. by the intravenous route, the compounds dilate the coronary arteries and arterioles, increasingthe heart blood flow. The compounds are therefore valuable-in the treatment of myocardial ischemia dueto organic or func+ tional decrease in the caliber of-thecoronary vessels.

The new compounds are readily evaluated by measuring .theirefiect upon the isolated perfused rabbit heart (Lange'ndorffsmethod), in which the coronary ves sels. are constricted by the action of beta-hypophamine or naphazoline. A very dilute aqueous solution of known concentration is prepared from a sample. of

or. as; an acid-addition salt.

through theIabbit' heart previously constricted by'a given amount of. beta-hypophamine added to thepcrfu'sion EXAMPLE 1 (a) Methylcinnamic acid A mixture of 228.8 g. of malonic acid 160 cc. of dry pyridine, 240 g. of m-tolualdehyde (containing some and p-tolualdehyde) and 2.0 cc. of dry piperidine was heated to 60 C. and then gradually heated further over a period of three hours'at 105 C. After another hour at 105 C. the reaction mixture was cooled, about one liter of benzene was added followed by 250 cc. of concentrated hydrochloric 'acid in 250 cc. of water. The mixture was shaken and the layers were separated. The benzene layer was washed with water, with sodium carbonate solution and again with water. Concentrated hydrochloric acid was added to the sodium carbonate extracts to the point of incipient precipitation, but maintaining the solution still on the alkaline side. The solution was heated nearly to boiling, decolorized with activated charcoal and filtered. The filtrate was then acidified to Congo red with concentrated hydrochloric acid and the precipitated material was collected by filtration, giving 259.7 g. of 3-methylcinnamic acid (containing some 2- and 4-methylcinnamic acid). The methylcinnamic acid was further purified by recrystallization from dilute ethanol, obtaining a product with the M. P. 93-98 C.

i (b) p-(methylcyclohexyl)propionic acid A solution of 48.6 g. of 3-methylcinnamic acid, M. P. 93-98 C., containing some 2-methy1 and 4-methylcinnamic acid, in 750 cc. of glacial acetic acid was hydrogenated in the presence of 1.2 g. of platinum oxide catalyst at an initial pressure of 515 lbs. per sq. inch. After five and one-half hours the theoretical quantity of hydrogen had been taken up, the catalyst was removed by filtration, the filtrate concentrated in vacuo and the residue distilled. The fraction boiling at l05-106 C. (0.08-9.11 mm.) was collected, giving 48.7 g. of 5- (methylcyclohexyl)propionic acid (mixture of 2-, 3- and 4-methyl and cis and trans isomers).

(c) S-(methylcyclohexyl)propanol A solution of 60.0 g. of S-(methylcyclohexyl) propionic acid, obtained as described above in part (b), in 100 cc. of dry ether was added dropwise over a fifty minute period to a suspension of 20.2 g. of lithium aluminum hydride in 300 cc. of dry ether, while allowing-the solution to reflux gently. The reaction mixture was cooled, 50 cc. of water was added followed by 500 cc. of concentrated hydrochloric acid. The aqueous layer Was separated, and the ether layer was washed with sodium carbonate solution and dried over anhydrous calcium sulfate. The ether solution was concentrated and distilled giving 51.4 g. of 3-(methylcyclohexyl)propanol (mixture of 2-, 3- and 4-methyl and cis and trans isomers), B. P. 75-76.5 C. Y (0.4 mm.), n =l.4649.

'(d) 3-(methylcyclohexyl)propyl bromide aeaaaao centrated ammonium hydroxide. The petroleum ether solution was dried over anhydrous calcium sulfate, concentrated and distilled, collecting the material boiling at 6266 C. (0.5 mm). This material was redistilled, giving 58.5 g. of 3-(methylcyclohexyl)propyl bromide (mixture of 2-, 3- and 4-methyl and cis and trans isomers), B. P. 56.5-59.5 c. 0.21 mm.), :1482.

Analysis.Calcd. for C H Br: C, 54.80; H, 8.74; Br, 36.46. Found: C, 55.20; H, 8.66; Br, 36.23.

(e) Z-hydroxyethyl-bis[3-(methylc'yclohexyl)propyllamine A mixture of 43.8 g. of 3-(methylcyclohexy1)propyl I bromide, obtained as described above in part (d), 6.1 g.

of Z-aminoethanol, 12.7 g. of anhydrous sodium carbonate; and 75 cc. of absolute ethanol was heated in an autoclave with shaking for eight hours at 142146 C. The

. reaction mixture was cooled and concentrated by distillation. The residue was dissolved in benzene, and the benzene solution was washed with 10% sodium carbonate solotion and with water and dried over anhydrous calcium sulfate. The benezene solution was concentrated invacuo, and the residue was stirred several times with (23.61 g.) was collected and redistilled, giving 2-hydroxyethyl-bis [3-(methylcyclohexyl)propyl]amine (mixture of 2-, 3- and 4-methyl and cis and trans isomers), B. P. 161-1635 C. (0.11-0.12 mm), n =1.4848.

,Analysis.Calcd. for C H NO: C, 78.27; H, 12.84;

. N, 4.15. Found: C, 78.50; H, 12.84; N, 4.22.

2-hydroxyethyl-bis 3-(methy1cyclohexyl) propyll amine has a coronary dilator activity forty times that of papaverine when measured on the isolated rabbit heart.

EXAMPLE 2 2-hydroxyethyl-bis[3-(3-methylcyci0hexyl)pr0pyl] amine When the same series of reactions described above in Example 1 was carried out, using pure 3-methylcinnamic acid (free of the 2- and 4-methyl isomers), M. P. 118l19 C., the following compounds were successively obtained: ,8-(3-methylcyclohexyl)propionic acid, B. P. 129130 C. (2 mm), n =1.4608; 3-(3-methylcyclohexyl)propanol, B. P. 105 C. (4 mm), n =l.4619; 3-(3-methylcyclohexyl)propyl bromide, B. F. 95 C. (4 mm.) n =1.4820; and 2-hydroxyethyl-bis [3-(3-methylcyclohexyl)propyl]amin'e (mixture of cis and trans isomers), B. P. 157 C. (0.04 mm.), 11 =1.483O.

If in the above examples 3-methylcinnamic acid is replaced by 2-ethylcinnarnic acid, 3-propylcinnamic acid or 4-butylcinnamic acid (prepared, respectively, by condensing Z-ethylbenzaldehyde, 3-propylbenzaldehyde or 4-butylbenzaldehyde with malonic acid according to the Knoevenagel reaction) and carried through the same series of reactions, there can be obtained, respectively, 2-hydroxyethyl-bis [3-(2-ethylcyclohexy1) propyl] amine, 2- hydroxyethyl bis[3 (3 propylcyclohexyl)propyl]- amine, or Z-hydroxyethyl-bis 3-(4-butylcyc-lohexyl) propyl] amine.

. EXAMPLE 3 (a) cis-fi- (3-methylcyclohexyl propionamide A mixture of 102.1 g. of ,8-(3-methylcyclohexyD- propionic acid .(see Example 2) and 107.1 g. of thionyl chloride was kept at room temperature for twenty-four hours. The excess thionyl chloride was removed by distillation in vacuo, last traces of which were removed by addition of two cc. portions of dry benzene and Concentration ofthe reaction mixture in vacuo. The residue was added to 800 cc. of concentratedammonium hydroxide and rapidly stirred at a temperature of 10'-0 C. The mixture was stirred .forone h'our,- and the solid material was collected by filtration, washed with Water anddried, giving. 98:5 'g. of p=(-3-methy1cyclo-.- hexyl)propionamide, M. P. 78-82 C. The lattermat'e rial was repeatedlyrecrystallized from 50%. methanol Until the melting point'had beenraised to90-91- CL, whichmaterial comprisedrthepure cis-isomer. j

(b) cis-B (-3 methylcy clohexyl) propionic acid cis-fi-(3-methylcyclohexyl)propionamide (33.9' g. prepared as described above inpart (a) was dissoived in concentrated sulfuric acid; The sulfuric acid solution was cooled to.-5- C., and asolutionof35 g. of sodium nitrite in 140 cc. of water was dropped under the-surface offthe sulfuric acid. solution with-stirring. over-a -period of. one and one-half. hours. The mixture was stirred for an'additional one-half hour then carefully diluted with :350 cc. of.water untilthe-temperature reached 50 C., and kept at 50- 60 C. for one-half hour. One kilogram of ice was added to the mixture which was then extracted with petroleum'ether (Skellysolve B),

When the cis-,S-(S-methylcyclohexyl)propionic' acid,

obtained above in part (b), was carried through the same series of reactions described in Example 1; parts'.(c), (d) and (e), the following compounds were'ob'tained': cise3j- '(3-m ethylcycloh exyl)propanol, B. P. 101-102 C. (4 mm.), n =1.4612; cis-3-(3-methylcyclohexyl)propyl bromide, B. P. 91 C. (4mm), n =1.4811; audcis= 2--*hydroxyethyl bis[3'- (3 --methylcyclohexyl)propyl]: amine, B; P. 151-152 C.(0.035' mm.), n =1.4822.

Analysis.Calcd, for C H NOr C, 78.27; 'I-I,. 12.84; N, 4.15. Found: C, 77.89; H, 12.58;N, 4.14;

V I EXAMPL E4 (a) fl-(4-methycyclohexyl)propionic acid was prepared from 121.5 g. of 4-methylcinnamic acid and 4.0g.

methylcyclohexyl )propanol (mixture. of. cisand trans isomers), B. P. 75-7 6 C. (0.72-0.82 mm.), n 5==1.4632,

(c) 3-(4-methylcyclohexyl)propyl bromide was prepared'from 98 g. of 3-(4-methylcyclohexyl)propanol'and hydrogen bromide according to the manipulative procedure described above in Example 1, part ((1). There was thus obtained 128 g. of 3-(4-methylcyclohexyl)- propyl bromide (mixture of cis and trans isomers), B. P. 80-81.5 C. (1.5 mm.) n =1.4832.'

A'nalysis.Ca1cd. for C H Br: C, 54.80; H, 8.74; Br,

36.46. Found: C, 54.74; H, 8.68; B1, 36.1.

a Z-hyarOxyeZhyI-bisi3-(4-methylcycl0- hexyl pxopyl amine A. mixture of 65.7Ig. of 3-(4-methylcyclohexyl)propyl bromide, 9.15 g. of '2-arninoethanol, 19.11. g. of anhydrous sodium carbonate. and 70" cc. of absolute ethanol was heated in an autoclave for eight hours at 142-147 C, The reaction. mixture was worked up according, to the manipulative procedure described'abovejn Example 1, part" (c) and the product was distilled, I The fraction 4 jExAMP E s (a) 'Benzyl-bis[3-(4-methylcycl0hexyl)propyllamine Asolfitibnof 16.05 grof-benzylaminein 50 cc. of'absolute ethanol was added-over a one hour period to a mide,2 1.2 g. of anhydrous sodium carbonate and cc. of absolute ethanol. The-mixture was refluxed for seven and'one-half hours afterthe' addition of amine" was c mp1eted',-and was allowed to stand overnight. The mixturefwas extracted with' benzene and the benzene extracts were washed with 10% sodium carbonatesolution -and '10% sodium hydroxide-solution and with water. The benzene solution was dried and concentrated, and the residue was stirred with petroleum ether (Skellysolve A). and the clear solution decanted andconcentrated': The residue was distilled and the fraction boiling;;at.1-7-7180' C. (0.05. mm.) (34.46 g.) wasscollected andrredistilled, giving:v benzyl-bis [3- (4-methylcyclohexyl )5- pr'opyllamine (mixture. of cis and trans isomers), B. P. 181 0.. (0.09 mm.), n =1.5.059.

Analysis.Calcd: for C H; N: C, 84.52; H, 11.82; N, 3.65. Found: C',.84.53; H, 11.77;.N,.3.64."

('b) Bisli3-('4-methylcyclohexyl)propyllamine ing;solid collected, dried and recrystallized from acetone gave the hydrochloride salt, M. P. 186.5188 C.

(c) Hydroxymethylbis[3 (4 methylcyclohexy1)- propyHamine can be prepared by treating bis[3'-(4'- methylcyclohexybpropyl]amine with formaldehyde underalkaline conditions,.for'example in the presence of sodiumcarbonate.

EXAMPLE 6 Z hydmxyethyI-bis (3-cyclohexylpropyl) amine Amixtureof 82.06 g, of 3.-cyclohexy1propyl bromide; 122 g. of Z-aminoethanol, 23.3 g. of anhydrous sodium carbonate and 250 cc. of absolute ethanol was refluxed fortwelve hours. Theireaction mixture was worked up according to the manipulative procedure givenabove in Example 1 part. (e). The. productwas distilled giving- 44.4' g.- of ZEhydroxyethyI-bis(3-cyclohexylpropyl)amine; B. PL. 145-147 C. (0.05-0.07 mm.), n =1.4872.

Analysis;Ca1cd. for C H NO: C, 77.60; H, 12.70; N, 4.53. Found: C, 78.06; H, 12.55; N, 4;4-8.

, 3-cyclohexylpropyl-[1,1 bis(hydroxymethyl)propyl]: v I -.amine- 1 A mixture of 61.541g. of 3-cyclohexy1propyl bromide;

17.87 g. of 1,1-bis(hydroxymethyl)propylamine. 17.5 g. of anhydroussodium carbonate and 200 cc. of absolute Ethanol was refluxed for23 hours. The reaction mixture was worked up according to the manipulative procedure given above in Example 1, part (e), and the product distilled. The fraction boiling at 150-452 C. (0.06-0.07 mm.) (33.36g.) was collected and redistilled, giving crude 3 cyclohexylpropyl' [1,1 bis(hydroxymethyl)- propyllamine, B. P. 1136.5137 C. (0.03 mm), n =1.4882912. The latter material wasdissolved in chloroform and extracted with dilute hydrochloric acid. The hydrochloric acid" extracts were made basic with potassium'carbonate and extracted with chloroform. The chloroform extracts were concentrated and the residue crystallized from ethyl acetate, giving pure 3-cyclohexylpropyl 1,1 bis(hydroxymethyDpropyllamine, M. P. 49.5-52" C. V V g W Analysis. Calcd. for C NO C, 69.09; H, 12.01; N, 5.76. Found: C, 6 9 .33; H, 11.73; N, 5,75.

The crude product obtained above contained some of the tertiary amine, bis(3-cyclohexylpropyl)-[1,1:bis- (hydroxymethyl)propylJamine. Larger quantifies of the latter can be obtained by longer heating (several days) of the reaction mixture. I,

. 7 EXAMPLE 8 I Bi.s"(3- cyclohexylpropyl) -2,3-dihyziroxypropylamine V A mixture of 30.53 g. of bis(3-cyclohexylpropyl)amine (prepared by hydrogenolysis of benzyl-bis(3-cyclohexylpropyl)amine, B. P. 154-156 C. (0.03 mm.) according EXAMPLE 9 r 3 cyclohexylpropyl [tris(hydr oxymethyl)methyflamine and bis(3 cyclohexylpropyl) [tris(hydr'xymethyl)- methyl] amine r A mixture of 61.54 g. of 3-cyclohexylpropyl bromide, 18.17 g. of tris[hydroxymethyl]methylamine, 17.5 g. of anhydrous sodium carbonate and 200 cc. of absolute 7 ethanol was refluxed for 112 hours. The reaction mixture was concentrated in vacuo and the residue was extracted with chloroform. The chloroform extracts were Washed with water and then with several portions of dilute hydrochloric acid. The chloroform solution (solution A) was separated from the aqueous acid layer, and the combined acid extracts were made basic with sodium carbonate and extracted with chloroform (solution B).

chloroform solution A was concentrated in vacuo and the residue stirred with petroleum ether (Skellysolve A) and the solid material was collected by filtration and amounted to 22.15 g. of the hydrochloride salt of bis(3- cyclohexylpropyl) [tris(hydroxymethyl)methyl]amine. The latter was dissolved in chloroform and the solution was washed with sodium carbonate solution, the chloroform layer separated and concentrated. .The residue was recrystallized from acetone, giving 16.8 g. of bis(3-cyclohexylpropyl) [tris (hydroxymethyl) methyl] amine, M. P. 110.5 111.5 C.

Analysis.-Calcd. for C H NO C, 71.49; H, 11.73; N, 3.79. Found: C, 71.69; H, 11.45; N, 3.78.

Bis 3-cyclohexylpropyl [tris (hydroxymethyl) methyl] amine (200 mg.) was dissolved in 4 cc. of an aqueous solution c0ntaining'59.6 mg. of ethanesulfonic acid, thus obtaining asolution of the ethanesulfonate salt with pH 4.5. V -A"mixture of 11.07 g. of bis(3-cyclohexylpropyl)-[tris (hydroxymethynmethyll amine and 5.76 g. of quinic acid in 65 cc. of absolute ethanol was heated until solution was complete. The solution was diluted with about 250 cc. of ether, cooled,, and'the product whichhad separated was collected byfiltration, giving 16.2 g. of the quinate saltof bis(3 4 cyclohexylpropyl) [tris(hydroxymethyl)- methyllamine, M. P. 119-120? C.

Chloroform solution B was concentrated and the residue was recrystallized from acetone, giving 12.45 g. of 3-cyclohexylpropyl [tris(hydroxymethyl)methyl] amine, M. P. 86-88" C. Further purification gave a product with the M. P. 91-93? C. V

Analysis.-Calcd. for C H NO3: C, 63.63; H, 11.09; N, 5.71. Found: C, 64.00; H, 10.96; N, 5.67.

EXAMPLE 10 3 (3 methylcyclohexyDpropyl [tris(hydr0xymethyl)- methyl] amine and v bis[3-(3-methylcyclohexyl) propyl] [tris(hydroxymethyl) methyl] amine A mixture of 19.7 g. of 3-(3-methylcyclohexyl)propyl bromide (see Example 2), 5.4 'g. of tris(hydroxymethyl)- methylamine, 5.7 g. of anhydrous sodium carbonate and cc. of absolute ethanol was refluxed for 53 hours. The crudesolid product, 11.5 g., M. P. 59-61 C., was isolated, essentially as described above in Example 1, part (e), and dissolved in a solution of 10 cc. of concentrated sulfuric acid in 50'cc.,of water. The solution was diluted with 300 cc. of water and cooled in an ice-bath. The gum which separated was collected by filtration and stirred with 14% ammonium hydroxide solution. The resulting free base was collected by filtration and recrystallized from acetone, giving 1.9 g. of bis[3-(3-methylcyclohexy1)- propyl]-[tris(hydroxymethyl)methyll amine, M. P. 97- 99 C. A. further recrystallization from acetone gave a sample with the M. P. 99.5100.5 C.

Analysis.Calcd. for C24H47NO3: C, 72.49; H, 11.91; N, 3.52. Found: C, 72.68; H, 12.19; N, 3.51.

The filtrate from the crude tertiary amine sulfate contained the soluble secondary amine sulfate. This filtrate was saturatedwith potassium carbonate, and the gummy material which separated was collected by filtration, dis solved in chloroform, concentrated in vacuo, and the residue (9.0 g.) was recrystallized from acetone, giving 3 (3 methylcyclohexyl)propyl [tris(hydroxymethyl)- methylJamine, M. P. 68-69 C.

Analysis. -Calcd. for C H NO C, 64.82; H, 11.27; N, 5.40. Found: C, 65.19; H, 11.08; N, 5.40.

We claim:

1. A compound selected from the class consisting of amines having the formula wherein C H is a cyclohexane ring, R is selected from the group consisting of hydrogen and lower-alkyl groups, and R is a lower-alkyl group bearing from one to three hydroxy groups which, if plural, are attached to difierent carbon atoms; and acid-addition salts thereof the anions of which do not increase the toxicity of the compound toward animal organisms.

2. Hydroxy-lower-alkyl-bis(3-cyclohexylpropyl)amines having from one to three hydroxy groups which, if plural, are attached to different carbon atoms of the lower-alkyl group.

3. Hydroxy-lower-alkyl-bis[3-(lower-alkylcyclohexyl)- propyllamines in which the hydroxy-lower-alkyl group contains from one to three hydroxy groups which, if plural, are attached to diiferent carbon atoms.

4. Mono-hydroxy-lower-alkyl-bis(3-cyclohexylpropyl)- amines. I i

5. Di-hydroxy-lower-alkyl bis(3 cyclohexylpropyl)- amines in which the hydroxy groups are attached to different carbon atoms of the lower-alkyl group.

6. Tri-hydroxy-lower-alkyl bis(3 cyclohexy1propy1)- amines in which the hydroxy groups are attached to different carbon atoms of the lower-alkyl group.

7. 2 hydroxyethyl-bis[3-(3-methy1cyc1ohexy1)propy11- amine.

8. 2 hydroxyethyl-bis[3-(4-methylcyc1ohexy1)propyl] amine.

9. Bis(3 cyclohexylpropyl) 2,3 dihydroxypropylamine.

10. Bis(3 cyclohexylpropyl) [tris(hydroxymethy1)- methyl] amine.

11. The process for preparing a hydroxy-lower-alkylbis(3-cyclohexylpropy1)amine having from one to three hydroxy groups which, if plural, are attached to different carbon atoms of the lower-alkyl group, which comprises heating a 3-cyclohexylpropy1 halide with a hydroxy-loweralkylamine in the presence of an acid acceptor.

12. The process for preparing bis(3-cyclohexylpropy1)-[tris (hydroxymethyl)methyl] amine which comprises heating a 3-cyc1ohexylpropyl halide with tris(hydroxymethyl)methy1amine in the presence of an acid acceptor.

13 Z-hydroxyethyl-bis (3-cyc1ohexy1propyl) amine.

14. Bis[3-(3-methylcyclohexyl)propyl] [tris(hydroxymethyl methyl] amine.

References Cited in the file of this patent UNITED STATES PATENTS 2,180,344 Blicke Nov. 21, 1939 2,226,160 Dietrich Dec. 24, 1940 2,278,123 Heyn Mar. 31, 1942 FOREIGN PATENTS 404,674 Great Britain Ian. 19, 1934 U 5. DEPARTMENT OF COMMERCE PATENT OFFICE CERTIFICATE @F QRRECTIQN March 25 1958 Patent No, 2,828,340

William BO Dickinson et al.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Let oers Patent should read as corrected below.

Column 3, line 45, for "(0008 9011 mo) read m (oaoe ooll mm) e,

Signed and sealed this 6th day of May 1.958o

(SEAL) At test:

KARL AXLINE ROBERT c. WATSON Conmissione'r of Patents Atteating Officer 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF AMINES HAVING THE FORMULA 